Complex Molecules Research Articles

Combinatory Effect of Gemcitabine and 5‐Fluorouracil Investigated Through Chemoinformatics and Molecular Dynamics Simulation Against Breast Cancer

ABSTRACTCo‐delivering FDA‐approved drugs can be less harmful and boost biological activity by targeting different protein mechanism at same time. Gemcitabine and 5‐Fluorouracil (GE5F) adduct work together to destroy cancer cells and increase the efficacy in the fight against breast cancer. The basis set B3LYP/6‐311 G was utilized in this investigation to improve the structure of GE5F adduct. The natural bond analysis exhibited the intermolecular interactions of the GE5F adduct. Electronic transitions were seen to be π → π*, and theoretical calculations were performed for the ultraviolet to visible spectrum. The energy gap between HOMO and LUMO was used to study the GE5F adduct's structural stability and reactivity; the computed energy gap (ΔE) was 3.912 eV. The Mulliken charge population was assessed and the complex structure's electrostatic potential was established. Weak interactions of the GE5F were assessed using RDG analysis, and topological aspects were investigated using LOL and ELF analysis. Investigating the GE5F adduct's adsorption, distribution, metabolism, excretion, and toxicity properties, the results confirmed that GE5F adduct comes under the safety parameters being a drug‐likeness molecule. Molecular docking experiments were conducted using target proteins for breast cancer. The complex molecule had a higher binding affinity as indicated by the docking scores, which validated the better combinatorial interaction between gemcitabine and 5‐Fluorouracil. With − 9.4 kcal/mol, the complex molecule's strongest binding capacity was against PARP protein, and stable confirmation was observed through molecular dynamic simulation for 100 ns with four hydrogen bond interactions. These in silico finding will pave a way for in vitro and in vivo experiments with better enhancement of FDA approved drugs.

Lipoprotein (a) as a Cardiovascular Risk Factor in Controversial Clinical Scenarios: A Narrative Review

Lipoprotein (a) is a complex lipid molecule that has sparked immense interest in recent years, after studies demonstrated its significant association with several cardiovascular conditions. Lp(a) promotes cardiovascular disease through its combined proatherogenic, pro-inflammatory, and prothrombotic effects. While the measurement of Lp(a) has become widely available, effective methods to reduce its concentration are currently limited. However, emerging data from ongoing clinical trials involving antisense oligonucleotides have indicated promising outcomes in effectively reducing Lp(a) concentrations. This may serve as a potential therapeutic target in the management and prevention of myocardial infarction, calcific aortic stenosis, and cerebrovascular accidents. In contrast, the role of Lp(a) in atrial fibrillation, in-stent restenosis, cardiac allograft vasculopathy, and bioprosthetic aortic valve degeneration remains unclear. This review article aims to thoroughly review the existing literature and provide an updated overview of the evidence surrounding the association of Lp(a) and these cardiovascular diseases. We seek to highlight controversies in the existing literature and offer directions for future investigations to better understand Lp(a)’s precise role in these conditions, while providing a summary of its unique molecular characteristics.

One-pot synthesis of phenyl- and biphenyl-linked bis-pyrrolo[3,4-b]pyridin-5-ones via a pseudo-repetitive Ugi-Zhu-5CR coupled to a double cascade process (aza-Diels-Alder/N-acylation/decarboxylation/dehydration)

Fifteen new bis-pyrrolo[3,4-b]pyridin-5-ones were synthesized via a one-pot process composed by a pseudo-repetitive Ugi-Zhu-5CR coupled to a double cascade sequence (aza-Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration) in 39–77 % yields, and in short reaction times (only one hour per compound) despite the big size, symmetry and high complexity of the products. The reaction conditions were first optimized step-by-step, and then, the bis-heterocyclic products were synthesized in one-pot manner. It was observed that, formation of the corresponding imines and the double cascade process were carried out without external heating inputs, instead that only under constant stirring at room temperature. Reaction conditions turned out to be the friendliest (in terms of energy) with the environment in comparison with all previously published methodologies involving post-Ugi-Zhu reactions. Therefore, this work shows that pseudo-repetitive MCRs are more thermodynamically favorable compared to classic MCRs, and that they also allow rapid access to highly structurally complex molecules, exhibiting a high degree of symmetry that may play an important role in several fields of knowledge like optics, material science, agrochemistry, and medicinal chemistry.

Impact of C-H Cross-Coupling Reactions in the One-Step Retrosynthesis of Drug Molecules.

Pharmaceutical synthesis requires a diversity of chemical reactions. The discovery of new reactions enable novel retrosynthetic disconnections, potentially expediting access to complex molecules. This Synopsis demonstrates the use of enumerative combinatorics to find impactful underdeveloped reactions for drug synthesis. By mapping pharmaceutical target molecules onto available building blocks using just one retrosynthetic disconnection even if the requisite reaction is not yet known, we highlight the importance of site-selective C-H cross-coupling methods. This cheminformatics-driven retrosynthetic analysis identifies novel reaction methods of value to the synthesis toolbox.

Feature Selection Enhances Peptide Binding Predictions for TCR-Specific Interactions.

T-cell receptors (TCRs) play a critical role in the immune response by recognizing specific ligand peptides presented by major histocompatibility complex (MHC) molecules. Accurate prediction of peptide binding to TCRs is essential for advancing immunotherapy, vaccine design, and understanding mechanisms of autoimmune disorders. This study presents a novel theoretical method that explores the impact of feature selection techniques on enhancing the predictive accuracy of peptide binding models tailored for specific TCRs. To evaluate the universality of our approach across different TCR systems, we utilized a dataset that includes peptide libraries tested against three distinct murine TCRs. A broad range of physicochemical properties, including amino acid composition, dipeptide composition, and tripeptide features, were integrated into the machine learning-based feature selection framework to identify key features contributing to binding affinity. Our analysis reveals that leveraging optimized feature subsets not only simplifies the model complexity but also enhances predictive performance, enabling more precise identification of TCR-peptide interactions. The results of our feature selection method are consistent with findings from hybrid approaches that utilize both sequence and structural data as input as well as experimental data. Our theoretical approach highlights the role of feature selection in peptide-TCR interactions, providing a powerful tool for uncovering the molecular mechanisms of the T-cell response and assisting in the design of more advanced targeted therapeutics.

The Role of the Working Fluid and Non-Ideal Thermodynamic Effects on Performance of Gas Lubricated Bearings

Abstract Small-scale turbomachinery operating at high rotational speed is a key technology for increasing the power density of energy and propulsion systems. A notable example is the turbine of an organic Rankine cycle turbogenerator for thermal recuperation from prime engines and industrial processes. Such systems typically operate with organic compounds characterized by complex molecular structures, to allow the design of efficient fluid machinery and flexibility in matching the heat source and sink temperature profiles. Gas bearings are considered advantageous compared to traditional oil-lubricated rolling element bearings for supporting the turbine rotor, enabling greater machine compactness and reduced complexity, and to avoid contamination of the working fluid. In certain operating conditions, however, the lubricant of the bearing is in thermodynamic states near the saturated vapor line or in the vicinity of the fluid critical point whereby non-ideal effects are relevant and may affect bearing performance. This work investigates the physics of thin film flows in gas bearings operating with fluids made by complex molecules. The influence of non-ideal thermodynamic effects on gas bearing performance is discussed by analysis of the fluid bulk modulus. Reduced values of the non-dimensional bulk modulus near the critical point or saturated vapor line decrease bearing performance. The main parameter characterizing the influence of molecular complexity on bearing performance is shown to be the acentric factor. For complex fluids with large acentric factors, the impact of non-ideal thermodynamic effects on non-dimensional bearing load capacity and rotor-dynamic characteristics is less pronounced.

Isolation and purification of DNA double-strand break repair intermediates for understanding complex molecular mechanisms.

Branched DNA molecules are key intermediates in the molecular pathways of DNA replication, repair and recombination. Understanding their structural details, therefore, helps to envisage the mechanisms underlying these processes. While the configurations of DNA molecules can be effectively analysed in bulk using gel electrophoresis techniques, direct visualization provides a complementary single-molecule approach to investigating branched DNA structures. However, for microscopic examination, the sample needs to be free from impurities that could obscure the molecules of interest, and free from the bulk of unwanted non-specific DNA molecules that would otherwise dominate the field of view. Additionally, in the case of recombination intermediates, the length of the DNA molecules becomes an important factor to consider since the structures can be spread over a large distance on the chromosome in vivo. As a result, apart from sample purity, efficient isolation of large-sized DNA fragments without damaging their branched structures is crucial for further analysis. These factors are illustrated by the example of DNA double-strand break repair in the bacterium E. coli. In E. coli recombination intermediates may be spread over a distance of 40 kb which constitutes less than 1% of the 4.6 Mb genome. This study reveals ways to overcome some of the technical challenges that are associated with the isolation and purification of large and complex branched DNA structures using E. coli DNA double-strand break repair intermediates. High-molecular weight and branched DNA molecules do not run into agarose gels subjected to electrophoresis. However, they can be extracted from the wells of the gels if they are agarose embedded, by using β-agarase digestion, filtration, and concentration. Furthermore, a second round of gel electrophoresis followed by purification is recommended to enhance the purity of the specific DNA samples. These preliminary findings may prove to be pioneering for various single-molecule analyses of large and complex DNA molecules of DNA replication, repair and recombination.

Direct recognition of an intact foreign protein by an αβ T cell receptor

αβ T cell receptors (αβTCRs) co-recognise antigens when bound to Major Histocompatibility Complex (MHC) or MHC class I-like molecules. Additionally, some αβTCRs can bind non-MHC molecules, but how much intact antigen reactivities are achieved remains unknown. Here, we identify an αβ T cell clone that directly recognises the intact foreign protein, R-phycoerythrin (PE), a multimeric (αβ)6γ protein complex. This direct αβTCR–PE interaction occurs in an MHC-independent manner, yet triggers T cell activation and bound PE with an affinity comparable to αβTCR–peptide–MHC interactions. The crystal structure reveals how six αβTCR molecules simultaneously engage the PE hexamer, mediated by the complementarity-determining regions (CDRs) of the αβTCR. Here, the αβTCR mainly binds to two α-helices of the globin fold in the PE α-subunit, which is analogous to the antigen-binding platform of the MHC molecule. Using retrogenic mice expressing this TCR, we show that it supports intrathymic T cell development, maturation, and exit into the periphery as mature CD4/CD8 double negative (DN) T cells with TCR-mediated functional capacity. Accordingly, we show how an αβTCR can recognise an intact foreign protein in an antibody-like manner.

Research Progress of Deep-Red to Near-Infrared Electroluminescent Materials Based on Organic Cyclometallated Platinum(II) Complexes.

In recent years, the near-infrared (NIR) light-emitting materials have attracted increasing attention due to the broad application prospects in the fields of military industry, aerospace, lighting, display and wearable devices. As the transition metal complexes, platinum(II) complexes have been shown to emit luminescence efficiently in NIR organic light-emitting diodes because of the unique d8 electron structure. This structure ensures that the platinum(II) complex molecules exhibit a high planarity, variety of excited states, and strong intermolecular interactions. This review summarizes the research progress of deep red to NIR organic light-emitting materials based on platinum(II) complexes in recent years and provides a certain reference for the further design and synthesis of NIR platinum(II) complex luminescent materials with superior performance.

Experimental and theoretical studies of carbacylamidophosphate-La (III) complexes: Synthesis, crystal structure, antibacterial activity, electronic and morphology properties

The present study tries to contribute to the body of knowledge concerning the effects of O-donor ligands based on carbacylamidophosphate on the topology, geometry, and dimensions of relevant metal complexes. Accordingly, the octa-coordinated lanthanum (III) complex with formula, [La(L1)4Cl2]Cl (C1) (L1 = 4-NC5H4C(O)NHP(O)(NC6H12)2), has been synthesized and its crystal structure has been determined. In the crystal structure, C1 is C2-symmetrical, and there are separate [La(L1)4Cl2]+ cations and Cl- anions. In the complex molecule, the four L1 ligands adopt two anti- and two syn-chelating conformations. Moreover, two other carbacylamidophosphate-based lanthanide complexes La(L2)2(NO3)3 (C2) (L2 = PhC(O)NHP(O)(NH(tert‑C4H9))2)2(NO3) and La(L3)2(NO3)3(H2O)[(CH3)2CO] (C3) (L3 = (4-NO2C6H4CONHPO(NC4H8O)2) were considered and density functional theory computations, at the B3PW91 level, were performed to gain a deeper understanding of the structural and electronic properties in complexes (C1 - C3). Nano and micro-structures of (C’1 - C’3) were prepared by means of a sonochemical process to study how the reaction condition and non-covalent forces function in terms of the form as well as the size of the particles in these complexes. Thermal gravimetric analysis (TGA) and differential thermal analysis (DTA) were performed on compounds C’1- C’3. The Hirshfeld surface analysis and NCI method were used to show the effects of non-covalent interactions on the compounds’ morphologies. The antimicrobial activity of all selected compounds has been screened against two Gram-positive (Bacillus subtilis, Staphylococcus aureus) and one Gram-negative (Escherichia coli) bacteria by well diffusion method. The results indicated that all selected compounds did not show any antibacterial activity against bacteria as compared to standard drugs.

Asymmetric Alkylative Difunctionalization of Carbon–Carbon Double Bonds by Aliphatic C─H Bond Activation

AbstractThis paper highlights the latest advancements in asymmetric alkylative difunctionalization of carbon–carbon double bonds by utilizing aliphatic C─H substrates as alkyl radical precursors. By integrating different hydrogen atom transfer (HAT) processes with various transition metal catalytic systems, various alkane substrates can be efficiently converted into corresponding alkyl radicals, which then participate in radical additions to carbon–carbon double bonds followed by stereoselective functionalizations with a third component. These strategies leverage inexpensive, abundant, and readily available alkane feedstocks to rapidly construct complex chiral molecules, demonstrating high step and atom economy. This paper focuses on recent progress and applications in this area, provides a comprehensive perspective on current developments, and suggests future directions in alkane‐involved asymmetric transformations.

Prognostic value of a lactate metabolism gene signature in lung adenocarcinoma and its associations with immune checkpoint blockade therapy response.

Lung adenocarcinoma (LUAD) is a study that examines the prognostic value of lactate metabolism genes in tumor cells, which are associated with clinical prognosis. We analyzed the expression and clinical data for LUAD from The Cancer Genome Atlas database, using the GSE68465 dataset from the Gene Expression Omnibus and the MSigDB database. LASSO Cox regression and stepwise Cox regression were used to identify the optimal lactate metabolism gene signature. Differences in immune infiltration, tumor mutation burden (TMB), and response to immune checkpoint blockade (ICB) therapy were evaluated between groups. LASSO and Cox regression analyses showed an eight-lactate metabolism gene signature for model construction in both TCGA cohort and GSE68465 data, with higher survival outcomes in high-risk groups. The lactate metabolism risk score had an independent prognostic value (hazard ratio: 2.279 [1.652-3.146], P < .001). Immune cell infiltration differed between the risk groups, such as CD8+ T cells, macrophages, dendritic cells, mast cells, and neutrophils. The high-risk group had higher tumor purity, lower immune and stromal scores, and higher TMB. High-risk samples had high tumor immune dysfunction and exclusion (TIDE) scores and low cytolytic activity (CYT) scores, indicating a poor response to ICB therapy. Similarly, most immune checkpoint molecules, immune inhibitors/stimulators, and major histocompatibility complex (MHC) molecules were highly expressed in the high-risk group. The 8-lactate metabolism gene-based prognostic model predicts patient survival, immune infiltration, and ICB response in patients with LUAD, driving the development of therapeutic strategies to target lactate metabolism.

Single-atom editing with light.

A new reaction swaps an oxygen for a nitrogen in structurally complex molecules.

Machine learning tools used for mapping some immunogenic epitopes within the major structural proteins of the bovine coronavirus (BCoV) and for the in silico design of the multiepitope-based vaccines.

BCoV is one of the significant causes of enteritis in young calves; it may also be responsible for many respiratory outbreaks in young calves. BCoV participates in the development of bovine respiratory disease complex in association with other bacterial pathogens. Our study aimed (1) to map the immunogenic epitopes (B and T cells) within the major BCoV structural proteins. These epitopes are believed to induce a robust immune response through the interaction with major histocompatibility complex (MHC class II) molecules (2) to design some novel BCoV multiepitope-based vaccines. The goal is achieved through several integrated in silico prediction computational tools to map these epitopes within the major BCoV structural proteins. The final vaccine was constructed in conjugation with the Choleratoxin B toxin as an adjuvant. The tertiary structure of each vaccine construct was modeled through the AlphaFold2 tools. The constructed vaccine was linked to some immunostimulants such as Toll-like receptors (TLR2 and TLR4). We also predicted the affinity binding of these vaccines with this targeted protein using molecular docking. The stability and purity of each vaccine construct were assessed using the Ramachandran plot and the Z-score values. We created the in silico cloning vaccine constructs using various expression vectors through vector builder and Snap gene. The average range of major BCoV structural proteins was detected within the range of 0.4 to 0.5, which confirmed their antigen and allergic properties. The binding energy values were detected between -7.9 and -9.4 eV and also confirmed their best interaction between our vaccine construct and Toll-like receptors. Our in silico cloning method expedited the creation of vaccine constructs and established a strong basis for upcoming clinical trials and experimental validations. Our designed multiepitope vaccine candidates per each BCoV structural protein showed high antigenicity, immunogenicity, non-allergic, non-toxic, and high-water solubility. Further studies are highly encouraged to validate the efficacy of these novel BCoV vaccines in the natural host.

Selective Functionalization of Alkenes and Alkynes by Dinuclear Manganese Catalysts.

ConspectusAlkenes and alkynes are fundamental building blocks in organic synthesis due to their commercial availability, bench-stability, and easy preparation. Selective functionalization of alkenes and alkynes is a crucial step for the synthesis of value-added compounds. Precise control over these reactions allows efficient construction of complex molecules with new functionalities. In recent decades, second- and third-row precious transition metal catalysts (palladium, platinum, rhodium, ruthenium) have been pivotal in the development of metal-catalyzed synthetic methodology. These metals exhibit excellent catalytic activity and selectivity, enabling efficient synthesis of functionalized organic molecules. However, recovery and reuse of precious metals have long been a challenge in this field. In recent years, exploration of earth-abundant metal-catalyzed organic reactions has interested both academic and industrial researchers. The development of such catalytic systems offers a promising approach to overcome the limitations of precious metal catalysts. For example, manganese is the third most naturally abundant transition metal with minimal toxicity and excellent biocompatibility. It exhibits good catalytic activity in several organic reactions, including C-H bond functionalization, selective reduction, and radical reactions. This Account outlines our recent progress in dinuclear manganese catalysis for selective functionalization of alkenes and alkynes. We have established the elementary manganese(I)-catalysis in transmetalation with R-B(OH)2. This finding has enabled us to apply the catalyst for the selective 1,2-difunctionalization of structurally diverse alkenes and alkynes. Mechanistic studies suggest a double manganese center synergistic activation model, as superior to Mn(CO)5Br in some cases. In addition, we have developed a ligand-tuned metalloradical strategy of dinuclear manganese catalysts (Mn2(CO)10), bridging the gap between the organometallics and radical chemistry, highlighting the unique radical functionalization of alkenes. Interestingly, using the same starting materials, different ligands can deliver completely different products. Meanwhile, a cooperative catalysis strategy involving manganese and other catalysts (e.g., cobalt, iminium) has also been developed and is briefly discussed. For manganese/iminium synergistic catalysis, a new mechanism for migratory insertion and demetalization-isomerization in synergistic HOMO-LUMO activation was disclosed. This strategy expands the application of low-valent manganese catalysts for enantioselective C-C bond-forming reactions. New reaction discovery is outpacing mechanism studies for dinuclear manganese catalysis, and future studies with time-resolved spectroscopy will improve understanding of the mechanism. Based on these intriguing findings, the precise functionalization of alkenes and alkynes by dinuclear manganese catalysts will expedite a novel activation model to enable late-stage functionalization of complex molecules.

Alcohols as Alkyl Electrophiles for Deoxygenative Heck Reaction Enabled by Excited State Pd Catalysis.

Here, we present a general method for the photoinduced Pd-catalyzed deoxygenative Heck reaction of vinyl arenes with ortho-iodophenyl-thionocarbonate derived from alcohols. Mechanistic studies reveal that the deoxygenation involves a 5-endo-trig cyclization and fragmentation process, with radical addition identified as the rate-determining step in this transformation. This one-pot procedure demonstrates excellent selectivity for less hindered hydroxyl groups in diols, facilitating late-stage functionalization of complex molecules and scalability to gram-scale synthesis. The protocol highlights significant synthetic potential and can be extended to the cascade 1,1-difunctionalization of isocyanides and the intermolecular radical cascade cyclization of N-arylacrylamides.

Impact of Hydroxy-Aluminum and Extracellular polymeric substances interactions on waste activated sludge Dewatering: A molecular perspective

Al13 and Al30 are the dominant aluminum (Al) species in polyaluminium chloride commonly used for sludge dewatering. However, the presence of extracellular polymeric substances (EPS) in the waste activated sludge hinders the coagulation effectiveness of Al-based coagulants. This study focused on the effects and mechanisms of Al13 and Al30 on treating sludge EPS. From a bulk perspective, the dosing of two coagulants significantly reduced the dissolved organic carbon and various organic compounds, reflecting their efficacy in removing organic substances in EPS. Further molecular characterization was revealed by FT-ICR MS. Al13 was more effective in removing lipids, lignins, and sulfur-containing compounds compared to Al30. Al13 also demonstrated a pronounced removal in components enriched in oxygen atoms (10–20) and KMD(COO) (0.5–0.7), suggesting its ability to remove molecules across a broader range of unsaturation. After coagulation with Al13, the areas corresponding to Al2p1/2 and Al2p2/3 in the Al2p spectra were more prominent compared to those in the Al30-coagulated EPS. Therefore, Al13 can both remove complex and low molecule weight compounds through abound forms of adsorption sites, making it more efficient in releasing bound water compared to Al30.

A New Mechanism for Formation of Glycine from Glyoxylic acid: the Aza-Cannizzaro Reaction.

Glyoxylic acid and glycine are widely considered to have been important prebiotic building blocks. Several mechanistic routes have been previously examined for conversion of glyoxylic acid to glycine. Here we provide evidence for a new mechanistic path. Glycine is spontaneously formed from glyoxylic acid in ammonium-rich aqueous solutions at neutral pH; oxamic acid is generated as well. Hydride transfer from the glyoxylate-derived hemiaminal to the corresponding iminium ion appears to underlie this transformation. This proposed mechanism parallels the well-known Cannizzaro reaction mechanism, which leads us to suggest the designation "aza-Cannizzaro reaction." This discovery offers a new perspective on prebiotic nitrogen incorporation because glycine can be a source of nitrogen for more complex molecules, including other α-amino acids.

200 Years of The Haloform Reaction: Methods and Applications.

Discovered in 1822, the haloform reaction is one of the oldest synthetic organic reactions. The haloform reaction enables the synthesis of carboxylic acids, esters or amides from methyl ketones. The reaction proceeds via exhaustive a-halogenation and then substitution by a nucleophile to liberate a haloform. The methyl group therefore behaves as a masked leaving group. The reaction methodology has undergone several important developments in the last 200 years, transitioning from a diagnostic test of methyl ketones to a synthetically useful tool for accessing complex esters and amides. The success of the general approach has been exhibited through the use of the reaction in the synthesis of many different complex molecules in fields ranging from natural product synthesis, pharmaceuticals, agrochemicals, fragrants and flavouring. The reaction has not been extensively reviewed since 1934. Therefore, herein we provide details of the history and mechanism of the haloform reaction, as well as an overview of the developments in the methodology and a survey of examples, particularly in natural product synthesis, in which the haloform reaction has been used.

Synthesis of bisnitroepoxides and their applications in the synthesis of bis(thiazolidine-2-thiones), bis(dithiocarbamates), bis(xanthates) and bis(thiazoles)

Novel bis(nitroepoxides) were prepared based on terephthaldehyde and isophthaladehyde and their reactions with diversities of nucleophiles such as primary and secondary amine-based dithiocarbamic acids, xanthates, and ammonia-based dithiocarbmamates were investigated for the synthesis of bis(thiazolidine-2-thiones), bis(dithiocarbamates), bis(xanthates) and bis(thiazoles), respectively. It provides simple access to complex molecules in one step in high to excellent yields.